Stabilization of levo-3-(3,4-dihydroxyphenyl)-2-methylalanine with sodium bisulfite and sorbitol



States Patent Ol STABILIZATION OFLEX O-Sl-(BlA-DIHYDROXY- PHENYD-Z-METHYLALANINE WITH SODI- UM BISULFITE AND SORBITOL 3,526,698 Patented Sept. 1, 1970 also been observed that a loss of potency accompanies the oxidation and discoloration.

Accordingly, it is an object of this invention to prevent the oxidation of therapeutically active a-methyl-phenyl- Gerald R Pom Norfistown, Pa Wayne M. Grim, Herb 5 alanine compounds, It is another object of this invention ford Heath, England and Thomas L Macek, Jenkim to prevent such OXldalIIOII and at the same time prepare town Pa assignors to Merck and CO Inc Rahway a stable, oral, llqllld pharmaceutical formulation of an N.J., a corporation of New Jersey y -p ny nine.

No Drawing. Continuation-impart of application Ser. No. It is also an object of this invention to provide such a 1965- This application P 1963, pharmaceutical preparation in which the loss of potency 720,478 I accompanying oxidation of the ot-methyl-phenylalanine U S Cl C A611 27/00 1 Claim compound is reduced. Repeated opening of the containing bottle to withdraw a fractional amount for a single dose,

and the repeated entrance of atmospheric oxygen does 15 not result in a visible color change nor loss in potency. ABSTRACT OF THE DISCLOSURE Additional objects and advantages of the composition The therapeutic agent 1 ev dihy 0Xyphen01) 2 of the present invention will appear from the following methylalanine is made stable in oral, fluid pharmaceutical descnptlon and exalpp formulation by the addition of sodium bisulfite and now beenfllscoveredfilat by addmg to apharma' sorbitol. ceut cal formulatlon contammg an a-methyl-phenylalanine compound, sorbitol as a stabilizing agent, a watersoluble antioxidant, such as sodium bisulfite, and prefer- This application is a continuation-in-part of US. Ser. ably such a water-soluble antioxidant and a chelating No. 493,556, filed Oct. 6, 1965, now abandoned. agent, such as ethylenediamine tetraacetate disodium, and by adjusting the pH to an acidic level, such a stable, oral,

RELATED CASE liquid pharmaceutical formulation may be prepared. In the following test preparations, 5% by weight sus- Thrs invention relates to pharmaceutlcal compositions Pensions f 1evo 3 (3,4 dihydroxyphenyl) 2 methy1a1anine contftlnmg as an actwe mgredlfmt an j Y 'P in either distilled Water or sorbitol solution were prealanme P f More PQ' relates a pared. By sorbitol solution is meant the U.S.P. aqueous stable oral, llquid pharmaceutical formulation contaimng preparation containing in each 100 gm f 69 to 71 an y p l gm. of D-sorbitol of high purity. An equivalent amount The therapeutlcany actlve compounds known as of solid sorbitol may be substituted. One hundred ml.

d'methylphenylalanines and the Production thereof are portions of these suspensions, with the additional additives disclosed in the Pfister the disclosure shown, were placed in clear glass bottles and exposed to of which is incorporated herein by reference and made a the temperature conditions noted and the resulting color part hereof. These compounds have well-known therachanges, if any, were visually observed. Initially all of peutic utility. the preparations were milky White in appearance.

Zero days 21 days 103 days p rfiiaration Ingredient Color pH 37 C Room temp. 37 0. Room temp.

1 Distilled water (I) White 4.9 Grey White Black Black.

2 Sorbitol solution (11) "do 5.1 do Gre do Do.

3 1+0. 05% EDTAN82 (111)-- 6.0 Black Black do Do.

4 II+0.05 0 EDT a2 6.1 Grey Grey (10.. Do.

5 I+0. 3% NaHSOs (IV) 4.8 White White Yellow white Yellow white.

s II+0.3% NaHSOs..- 5.1 do do Wh' Do.

7-- I+III+IV Slightly yellow white.

2 II+III+IV 5.3 White.

Included in these compounds are those having the formulas: I

From Test Preparations 1 through 8, it can be observed that the incorporation in a pharmaceutical composition containing an ot-methyl-phenylalanine in sorbitol solution of an antioxidant such as sodium bisulfite, and preferably additionally a chelating agent such as ethylenediamine tetraacetate disodium, highly stable preparations may be prepared.

Preparation 2 shows by the color change that sorbitol alone is not able to protect the phenylalanine compound against deterioration. Preparation 5 shows that the antioxidant alone does not provide adequate protection. Preparation 6 shows that a combination of the agents, sorbitol solution and sodium bisulfite protects the phenylalanine compound against decomposition. It has also been observed by active ingredient assays that the composition of Test Preparation 8 after 103 days of storage is found to contain 5% more active ingredient than that of Test Preparation 7.

In practicing the invention the preparation should contain the following:

3 Table a-Methylphenylalanine compound-2l0% W./v. Sorbitol solution-55100% v./v.

Ethylenediamine tetraacetate disodium-'00.l% w./v. Distilled water-40% v./v.

HCl or NaOH suflicient to-pH 2 to 7.

To this preparation may or may'not be added desired coloring, flavoring, suspending, wetting and preservative agents. Equivalent agents, as mentioned below, may be substituted in this table and the following example. Representative embodiments of the composition of this invention are set forth as follows, parts being expressed as weight per volume or volume per volume, as noted.

EXAMPLE I Ingredient:

Levo-3 (3 ,4-dihydroxyphenyl) -2- methylalanine-5 w./v. Sodium bisulfite-0.3 W./v. Sorbitol solutionq.s.

Due to the sodium bisulfite the pH of this preparation is about 5.1. The preparation can be made more acid by adding N/ HCl or more basic by adding N/lO NaOH. A commercial product which would contain a suspending agent to avoid undesirable settling and include a preservative is the following:

EXAMPLE II Ingredient:

Levo-3- (3 ,4-dihydr0xyphenyl) -2- methylalanine5% w./v. Sodium bisulfite-0.3 w./v. Gum tragacanth0.4% W./v. Sorbic acid-0.1% w /v. Distilled water--22.0% v./v. Sorbitol solutionq.s.

Equivalent well-known suspending agents which will function in accordance with the composition of this invention are other hydrocolloidal gums, such as gum acacia and guar gum; polysaccharides, such as agar, algin and chondrus; modified cellulose, such as methyl cellulose, carboxymethyl cellulose and hydroxy methyl cellulose; proteins and clays.

Equivalent preservatives suchas benzoic acid may be utilized, and equivalent compatible surfactants, dyes and flavors may be utilized without departing from the spirit and scope of the composition of this invention as described and claimed herein.

Equivalent antioxidants are other inorganic sulfur compounds, such as sodium metabisulfate and sodium thio sulfate and sodium sulfitej organic sulfur compounds, such as thioglycerol, thioglycolic acid, cysteine, and thiourea acids, such as ascorbic acid and isoascorbic acid.

The invention contemplates that, if desired, any pharmaceutically acceptable wetting agent, coloring agent, or flavoring agent may be added. 4 1

What is claimed is: 1. A stable, "oral, liquid pharmaceutical formulation having the following approximate composition:

Ingredient:

Levo-3-(3,4-dihydroxyphenyl) -2- methylalanine5 W. N. Sodium bisulfite-0.3 w./v. Sorbitol solution-q.s.

References Cited UNITED STATES PATENTS 2,055,064 9/1936 Bockmiihl 424-310 2,647,928 8/1953 Stemple 424-329 2,868,818 1/1959 Pfister 424-330 2,887,435 5/1959 Witty 424330. 3,149,035 9/1964 Riegelrnan 424148 3,228,834 1/1966 Gans 424244 3,230,146 1/1966 Marcus 424330 OTHER REFERENCES Chem. Abst., 56, p. 9174b (1962). Chem. Abst., 57, p. 7443H (1962). ALBERT T. MEYERS, Primary Examiner S. I. FRIEDMAN, Assistant Examiner US. or. X.R. 

